The objective of this proposal is to continue our examination of the mechanism of antibody-mediated neutralization of picornaviruses and to initiate structural studies on the replication complex. Using a combination of molecular biology, crystallography, and cryo-electron microscopy, we are examining the structures of several different antibodies alone and complexed with human rhinovirus 14. Through these studies, we hope to elucidate the structural mechanism of antibody-neutralization, to ascertain the structural reasons for why antibodies neutralize with varied efficacies, and to address (and clarify) some of the current dogmas concerning neutralization. In addition, these studies help us to better understand other aspects of antibody structure/function relationships such as flexibility and somatic hypermutations. By better understanding what chemical interactions are required for recognition, and by identify the key structural processes involved in neutralization, we hope this work will aid the development of vaccines against other viral pathogens. We have also started work on the structure/function of the non-structural protein, 3A. This protein activates the viral RNA polymerase via an yet unknown mechanism and seems to be a target for a new anti-viral agent, enviroxine. Therefore, all of this proposed work is examining how one can control viral infections either by natural or pharmaceutical agents.